2 Epidemiology Common due to: Aging population—3-5% prevalence in population >75Relatively common incidence of bicuspid AoV (1-2% of population)Long latent period, asymptomatic progression from AVA 3-4 cm2 to 1.5 cm2Additional reduction in valve area from ½ to ¼ normal size usually results in symptoms
3 Pathophysiology Outflow obstruction results in: Concentric hypertrophy in response to increased LV pressures to maintain normal wall stress; initially preserved LVEDV and COWith increasing afterload from increasing obstruction, further hypertrophy results in:--increased O2 demand--decreased coronary perfusion pressure--intramyocardial arterial compression--interstitial fibrosis and diastolic dysfunctionUltimately resulting in myocardial ischemia and reduced contractilityAngina secondary to aboveDyspnea due to diastolic dysfunction and inadequate cardiac output in setting of fixed obstructionDizziness/syncope due to exercise induced vasodilation in setting of fixed output, baroreceptor abnormalities, arrhythmia (AF)Heart failure: advanced disease, low output state
4 Progression of ASMean pressure gradient increase up to 10 mm Hg/year (mean 7 mm Hg)Aortic valve area decrease of 0.12 ± 0.19 cm2/yearIndividual variability existsFeigenbaum’s Echocardiography, Sixth Edition, 2005, pp
5 Natural History Prognosis significantly worsens with onset of symptoms Average survival with symptom onset: less than 2-3 yearsIncreased risk of sudden death
6 Etiologies Nonvalvular: Subaortic Supravalvular Valvular: Calcific (7th or 8th decade)Bicuspid (4th or 5th decade)Rheumatic: more common in developing nations
7 Subaortic Stenosis Fixed vs. Dynamic (HOCM) Distinct morphologies of fixed obstruction:--Thin membrane (most common): typically seen proximal to aortic root/septum junction--Thick fibromuscular ridge--LVOT hypoplasiaOften associated with ARPathophysiology: LVOT abnormalities causing LVOT obstruction/fibrosis, LV hypertrophy, hyperdynamic function
8 Subaortic StenosisSimilar CW doppler velocity profiles for valvular AS and subaortic membraneLate systolic velocity peak with dynamic obstruction in HCM; change in velocity profile with provocative maneuversOtto CM, Textbook of Clinical Echocardiography, 3rd Edition, 2004, pp. 283.
9 Supravalvular AS: Etiologies 4 distinct inheritance patterns:Williams Syndrome: “elfin facies,” mental retardation, hypercalcemia, failure to thrive, renovascular hypertension, short statureLikely autosomal dominant inheritance; may be related to elastin gene mutation (chromosome 7q11.23)Autosomal dominant familial form (without features of Williams Syndrome)Sporadic form without family historyHomozygous familial hypercholesterolemia (FH):Autosomal dominant disorder; up to 44% have supravalvar ASLess frequent in heterozygotes, typically affecting adults
10 Supravalvular AS: Morphologies HourglassAortic medial thickening/disorganization causeconstricting annular ridgesuperior to sinuses ofValsalvaMost common subtypeMembranous: fibrous/fibromuscular diaphragm with small opening stretched across aortaDiffuse Hypoplasia
12 Supravalvular AS TEE Aortgraphy Surgical repair is definitive therapy Usually performed at lower gradient levels than in valvular AS to prevent long term sequellaeOutcomes better for focal disease than diffuse hypoplasiaYoun, HJ, Chung, WS, Hong, SJ. Heart 2002; 88:438.
14 Congenital Valvular AS: Unicuspid and Bicuspid Bicuspid Aortic Valve:Typically normal function in childhoodAortic stenosis presentation after 50 years of age20% develop aortic regurgitation between ages 10-40, may require AVRIncreased risk of endocarditisAssociated with dilated ascending aortaUnicuspid Aortic Valve:May cause severe obstruction in infancyMale:female 4:1Associated with coarctation, PDAMost common cause of fatal AS <1yr of ageLewin MB, Otto CM. Circulation 111: 832, 2005.
15 Rheumatic AS Fusion of commissures and cusps Leaflet vascularization, causing stiffening of cusps free bordersTypically regurgitant and stenoticRheumatic mitral disease nearly always present in patients with rheumatic AS
16 Calcific ASDisease process likely similar to vascular atherosclerosis: inflammatory and proliferative changesRisk Factors:1. Age2. Elevated LDL and Lp(a)3. Diabetes4. Hypertension5. Cigarette smokingCytokine release by infiltrating T-lymphocytes and macrophages promotes:1. Extracellular matrix remodelling2. Cellular proliferation3. Differentiation of subset of fibroblasts into myofibroblasts possessing smooth muscle cell properties4. Lipid accumulation (LDL, oxidized by macrophages)5. Subset of myofibroblasts differentiate into an osteoblast phenotype, capable of calcium nodules and bone formationFreeman RV, Otto CM. Circulation 111: 3316, 2005.
17 AS: Fluid DynamicsLaminar flow in LVOT proximal to stenotic valve (arrowheads)As blood nears stenotic orifice, flow accelerates in small zone proximal to valveIn stenotic orifice, narrowest high velocity laminar jet is formed downstream from the orifice (vena contracta)Vena contracta is smaller than actual orifice (magnitude of difference described by discharge coefficient, which depends on orifice geometry and inertial/sheer stress fluid properties)Non-laminar flow beyond the jet, with blood moving in multiple directions and velocitiesOtto CM. Textbook of Clinical Echocardiography, 3rd edition, pp. 278.
18 ΔP = ½ p (v22- v12) + p (dv/dt)dx + R(v) AS: Fluid DynamicsPressure gradient across stenotic valve is related to velocity in the jet, first described by Bernoulli in 1738, later refined by Euler, first applied to stenotic aortic valves by Hatle in 1979:ΔP = ½ p (v22- v12) + p (dv/dt)dx + R(v)ΔP Pressure gradient across valve (mm Hg)p Mass density of blood (1.06 x 103 kg/m3)v2 Velocity in stenotic jetv1 Velocity proximal to stenosis(dv/dt)dx Time-varying velocity at each distance along flowstreamR(v) Constant for viscous resistance
19 ΔP = ½ p (v22- v12) + p (dv/dt)dx + R(v) Modified BernoulliΔP = ½ p (v22- v12) + p (dv/dt)dx + R(v)Eliminating terms for viscous losses and acceleration, using known values for mass density of blood, and converting velocity to m/s yields modified Bernoulli equation:ΔP = 4(v22- v12)If proximal velocity is < 1 m/s, modified Bernoulli is further simplified:ΔP = 4v2
20 Mean Pressure Gradient ΔPmean = ΔPmax/ mm HgMean gradient is approximately 2/3 of the peak instantaneous gradient
21 Calculation of AVA Planimetry Gorlin Equation AVA=(CO)/(HR)(SEP)(44.3)(√mean gradient)Hakki Equation (simplfication of Gorlin)AVA=(CO)/(√peak gradient)Continuity Equation
22 AVA Calculation: Echocardiography vs. Invasive Hemodynamics Peak aortic and left ventricular pressures do not occur simultaneouslyMaximum instantaneous gradient is greater than peak-to-peak gradientEchocardiography and cardiac catheterization may yield discrepant results
23 Continuity Equation SVLVOT=SVAo CSALVOT x VTILVOT = CSAAo x VTIAo AVA = (CSALVOT x VTILVOT )/VTIAoLVOT diameter: Parasternal Long AxisVTILVOT: Pulsed doppler, apicalVTIAo: CW doppler, highest recorded velocitySimplified Continuity Equation:Assuming VTILVOT/VTIAo = VLVOT/VAo, and assuming circular outflow tract area,AVA = π(LVOT diameter)2/4 x VLVOT/VAo
24 Evaluation of AS Severity Maximal Aortic Valve Velocity:In asymptomatic AS patients, AoV velocity is strongest predictor of outcomes:≤3 m/s: death or AVR 8%/year3-4 m/s: 17% per year≥4 m/s: 40% per yearVmax (m/s)Severity≥4Severe3-4Moderate1.6-3Mild≤ 1.5Normal2006 AHA/ACC GuidelinesOtto CM, Burwash IG, Legget ME, et al. Circulation 1997; 95:
25 Evaluation of AS Severity Mean Gradient (mmHg)AVA (ACC/AHA) (cm2)AVA (BIDMC)(cm2)Normal<53-4Mild<25>1.5>1.2Moderate25-40Severe>40<1.0<0.8
26 Imaging Challenges Parallel intercept angle between ultrasound beam and aortic jet ensures maximal measured Ao velocity,as cos θ =1.Deviation from parallel underestimates jet velocity,which is squared in continuity equation, magnifyingthe error.Intercept angle of less than 15 degrees result inerror ≤ 5%.Multiple velocity measurements taken in multipleviews to ensure highest velocity measured.Multiple other high velocity systolic jets that maybe mistaken for AS:Mitral regurgitationTricuspid regurgitationVSDPulmonic stenosis
27 Imaging ChallengesLV outflow diameter measurement critical to accurate calculation of AVAArrhythmia: variability in velocity depending on stroke volume and preceding R-R interval
28 Challenges: Low Gradient AS Definition: Severe AS (AVA<1.0 cm2) with transvalvular pressure gradient <30 mm HgChallenge is to differentiate low gradient AS patients who will benefit from AVR (“true stenosis”) from those who will not“Psedostenosis:” symptoms due primarily to LV dysfunction rather than valvular diseaseGorlin and Hakki equations underestimate AVA when CO is low
29 Challenges: Low Gradient AS AS Assessment with LV Dysfunction
30 Therapy Surgical AVR is mainstay of treatment ACC/AHA Class IA Indications:Symptomatic severe ASSevere AS in patients undergoing CABG, aortic, or other heart valve surgerySevere AS with LVEF less than 50%Class IIA Indications:Moderate AS in patients undergoing CABG, aortic, or other heart valve surgeryClass IIBSevere AS in asymptomatic patients who have an abnormal response to exercise such as the development of symptoms or hypotensionSevere AS in asymptomatic patients with a high likelihood of rapid progression (as determined by age, valve calcification, and coronary heart disease).Severe AS in asymptomatic patients in whom surgery might be delayed at the time of symptom onsetMild AS in patients undergoing coronary artery bypass graft surgery in whom there is evidence, such as moderate to severe valve calcification, that progression may be rapidExtremely severe AS (aortic valve area less than 0.6 cm2, mean gradient greater than 60 mmHg, and aortic jet velocity greater than 5.0 m/sec) in asymptomatic patients in whom the expected operative mortality is 1 percent or less
31 Medical Therapy Association between AS progression and dyslipidemia Pohle K, Maffert R, Ropers D, et al. Circulation 2001; 104(16);AS calcification and progression increased in patients with serum LDL>130 mg/dLSALTIRE Trial: Scottish Aortic Stenosis and Lipid Lowering Trial, Impact on Regression (NEJM 2005; 352(23): )155 calcific AS patients (aortic jet velocity>2.5 m/s, calcification seen on TTE, mean AVA 1.03 cm2)Randomized to atorvastatin 80 mg vs. placeboNonclinical endpoints: change in aortic jet velocity and aortic valve calcium score25 month follow up: no difference in progression of aortic valve calcificationor rate of increase in aortic jet velocity
32 Medical TherapyRAAVE Study: Rosuvastatin Affecting Aortic Valve Endothelium(JACC 2007; 49(5): )NonrandomizedProspectively assigned moderate to severe AS patients (AVA cm2) to rosuvastatin 20 mg (61 patients with LDL>130 mg/dL) or no statin (60 patients with LDL<130 mg/dL)Endpoints: aortic valve area, aortic jet velocityRosuvastatin patients had significantly decreased rates of progression of both endpoints (-0.05 vs cm2/year; vs m/sec per year)SEAS Trial: Simvastatin and Ezetimibe in Aortic Stenosis(NEJM Sept 2, 2008)1873 mild-moderate AS patients (peak aortic jet velocity m/s)Randomized to 40 mg simvastatin plus 10 mg ezetimibe (944 pts) vs. placebo (949 pts)Primary outcome: composite of major cardiovascular events (death from cardiovascular causes, aortic-valve replacement, nonfatal MI, hospitalization for unstable angina pectoris, heart failure, coronary-artery bypass CABG, PCI, and nonhemorrhagic stroke)
33 SEAS--ResultsAortic-valve replacement occurred in 267 patients (28.3%) in treatment group and in 278 patients (29.9%) in placebo group (hazard ratio, 1.00; 95% CI, 0.84 to 1.18; P=0.97)
35 Adverse Events Significantly increased incidence of cancers in simvastatin-ezetimibe group
36 SEAS—Conclusions Conclusions: In patients with mild-to-moderate, asymptomatic aortic-valve stenosis and no traditional indications for lipid-lowering therapy at baseline, long-term, intensive lipid-lowering therapy with simvastatin and ezetimibe had no overall effect on the course of aortic-valve stenosisLipid-lowering therapy reduced risk of ischemic cardiovascular events, especially the need for CABGHigher incidence of cancer in the simvastatin–ezetimibe group requires further exploration in ongoing and future trials.
37 Percutaneous Aortic Valve First human case description 2002: 57-year-old man with calcific aortic stenosis, cardiogenic shock, subacute leg ischemia, and other noncardiac diseasesInitially successful implant (transseptal approach)Improved hemodynamicsPatient died of comorbid conditions 17 weeks after implantCribier A, et al. Circulation, Dec 2002; 106: 3006 – 3008Up to 500 patients worldwide have subsequently undergone implantationRestricted to symptomatic severe AS patients with contraindications for surgeryMay provide symptomatic relief for up to 2 yearsSafety and long term durability remain in questionEur J Cardiothorac Surg 2008;34:1-8
38 Edwards SAPIENTM Percutaneous Valve Equine pericardial trileaflet valve is sewn within a stainless steel frame. A fabric skirt covers the bottom third of the stent23 and 26 mm diameter sizes14.5 and 16 mm height, respectivelySteerable deflection catheter used to guide prosthesis to aortic valve position
39 Percutaneous Aortic Valve Rapid RV pacing reduces transvalvular pulsatile flow during device deploymentWebb, J. G. et al. Circulation 2006;113:
42 PARTNER Trial: Inclusion Criteria Placement of AoRtic TraNscathetER ValvesInclusion Criteria: Cohort A (surgical AVR vs. transcatheter AVR): High Risk1. Predicted operative mortality of 15% and a minimum STS score of 10.2. Mean aortic gradient by TTE within 30 days of procedure>40mmHg and/or jet velocity greater than 4.0 m/s or an initial aortic valve area (AVA) of <0.8 cm2 (indexed EOA <0.5 cm2).3. NYHA Functional Class II or greater.Cohort B (medical management including BAV vs. transcatheter AVR): Extremely High Risk1. All candidates for Cohort B of this study must meet # 2 and 3 above, and2. The subject, after formal consults by a cardiologist and two cardiovascular surgeons agree that medical factors preclude operation, based on a conclusion that the probability of death or serious, irreversible morbidity exceeds the probability of meaningful improvement. Specifically, the probability of death or serious, irreversible morbidity should exceed 50%.
43 PARTNER Trial: Exclusion Criteria 1. Acute MI 1month before intended treatment (defined as: STEMI, or NSTEMI with total CK elevation twice normal in the presence of MB elevation and/or troponin level elevation (WHO definition).2. Congenital unicuspid or bicuspid aortic valve.3. Mixed aortic valve disease (aortic stenosis and aortic regurgitation with predominant aortic regurgitation >3+).4. Any therapeutic invasive cardiac procedure, other than BAV, performed within 30 days of the index procedure, (or 6 months if the procedure was a drug eluting coronary stent implantation).5. Pre-existing prosthetic heart valve in any position, prosthetic ring, or severe (greater than 3+) mitral insufficiency.6. Blood dyscrasias as defined: Leukopenia (WBC<3000 mm3), acute anemia (Hb< 9mg %), thrombocytopenia (platelet count <50,000 cells/mm³), history of bleeding diathesis or coagulopathy.7. Untreated clinically significant coronary artery disease requiring revascularization.8. Hemodynamic instability requiring inotropic support or mechanical heart assistance.9. Need for emergency surgery for any reason.10. Hypertrophic cardiomyopathy with or without obstruction (HOCM).11. Severe ventricular dysfunction with LVEF <20.12. Echocardiographic evidence of intracardiac mass, thrombus or vegetation.13. Active peptic ulcer or upper GI bleeding within the prior 3 months.
44 Exclusion Criteria14. Known hypersensitivity or contraindication to aspirin, heparin, ticlopidine (Ticlid), or clopidogrel (Plavix), or sensitivity to contrast media, which cannot be adequately pre-medicated.15. Native aortic annulus size < 16mm or > 24mm per the baseline echocardiogram as estimated by the left ventricular outflow tract (LVOT).16. Patient has been offered but has refused surgery.17. Recent (within 6 months) cerebrovascular accident (CVA) or a transient ischemic attack (TIA).18. Renal insufficiency (Creatinine > 3.0) and/or end stage renal disease requiring chronic dialysis.19. Life expectancy < 12 months due to non-cardiac co-morbid conditions.20. Significant aortic disease, including abdominal aortic or thoracic aneurysm defined as maximal luminal diameter 5cm or greater; marked tortuosity (hyper-acute bend), aortic arch atheroma (especially if thick [> 5 mm], protruding or ulcerated) or narrowing (especially with calcification and surface irregularities) of the abdominal or thoracic aorta, severe “unfolding” and tortuosity of the thoracic aorta.21. Ileofemoral vessel characteristics that would preclude safe placement of 22F or 24F introducer sheath such as severe obstructive calcification, severe tortuosity or vessels size less than 7 mm in diameter.22. Currently participating in an investigational drug or another device study. [Note: Trials requiring extended follow-up for products that were investigational, but have since become commercially available, are not considered investigational trials].